First Therapy for Light Chain (AL) Amyloidosis: Subcutaneous Darzalex Combination Achieves 92% Hematologic Response Rate in Phase III Trial

June 14, 2020 News /BioValleyBIOON/ -- Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson (JNJ), recently announced positive results from the Phase III ANDROMEDA study at the 25th Annual Congress of the European Hematology Association (EHA). The study investigated subcutaneous Darzalex (Zhaokesi®, generic name: daratumumab) as first-line treatment for newly diagnosedDiagnosisThe first randomized Phase III study in patients with light-chain (AL) amyloidosis demonstrated that the Darzalex plus cyclophosphamide, bortezomib, and dexamethasone regimen (D-CyBorD) achieved a higher hematologic complete response rate compared with the cyclophosphamide, bortezomib, and dexamethasone regimen (CyBorD) (CR: 53% vs. 18%, p<0.0001). Furthermore, compared with the CyBorD regimen, the D-CyBorD regimen prolonged major organ deterioration–progression-free survival (MOD-PFS) and event-free survival (EFS). In this study, the safety profile of the combination therapy was consistent with subcutaneous Darzalex or

The safety profile of CyBorD was consistent.

Light Chain (AL) Amyloidosis is a rare, potentially fatal multisystem disease that occurs when the bone marrow produces abnormal antibody fragments known as light chains (AL). These light chains aggregate to form amyloid deposits, which accumulate in tissues and vital organs, interfering with normal organ function. As the disease progresses, many patients experience gradual degeneration of multiple organs, including the heart, kidneys, gastrointestinal tract, liver, and nervous system. Due to multi-organ involvement (particularly cardiac involvement) in the late stages, AL amyloidosisDiagnosisDiagnosis is often delayed, and the prognosis is poor. The median survival of patients with AL amyloidosis is estimated to range from 6 months to 3 years, depending on the patient population and the data source. Currently, there are no approved treatment regimens for this devastating disease.

ANDROMEDA (NCT03201965) is an ongoing, randomized, open-label, Phase 3 study investigating the efficacy and safety of subcutaneous Darzalex in combination with CyBorD for the treatment of patients with newly diagnosed AL amyloidosis. The study enrolled 388 newlyDiagnosisFor patients with AL amyloidosis who have measurable hematologic disease and involvement of one or more organs, the primary endpoint is the overall complete hematologic response rate (intent-to-treat/ITT). Secondary endpoints include major organ deterioration–progression-free survival (MOD-PFS), event-free survival (EFS), organ response rate, overall survival (OS), and time to hematologic response.

Research Results Indicate the Primary EndpointComplete Hematologic Remission Rate (CR)aspect,The D-CyBorD group was 53%, and the CyBorD group was 18% (odds ratio [OR] = 5.1; 95% CI: 3.2–8.2; p < 0.0001).. Furthermore, the D-CyBorD group exhibited a higherOverall Hematologic Response Rate (92% vs 77%)andVery good partial response or better response rate (≥VGPR: 79% vs. 49%). Among the 195 patients in the D-CyBorD group who achieved at least a very good partial response (VGPR), the median time from treatment initiation to achieving ≥VGPR/complete response (CR) was 17 days/60 days, whereas among the 193 patients in the CyBorD group who achieved at least VGPR, the median time from treatment initiation to achieving ≥VGPR/CR was 25 days/85 days.

Six-month organ response rate: the D-CyBorD group was nearly double that of the CyBorD group, including: cardiac response rate (42% vs 22%; p=0.0029) and renal response rate (54% vs 27%; p<0.0001). Furthermore, MOD-PFS (hazard ratio [HR]=0.58; 95% CI: 0.36-0.93, p=0.0224) and MOD-EFS (HR=0.40; 95% CI: 0.28-0.57, p<0.0001) favored the D-CyBorD group, demonstrating a significant delay in major organ deterioration, hematologic progression, or death, as well as improved event-free survival. Additionally, daratumumab in the D-CyBorD group was administered via subcutaneous injection, which helps limit intravenous fluid overload, an important therapeutic consideration in patients with cardiac involvement.

In the study, the most common grade 3/4 treatment-emergent adverse events (TEAEs) occurring in >5% of patients in the D-CyBorD group (compared with the CyBorD group) included: lymphopenia (13% vs. 10%), pneumonia (8% vs. 4%), diarrhea (6% vs. 4%), heart failure (6% vs. 5%), neutropenia (5% vs. 3%), and syncope (5% vs. 6%). The study demonstrated a lower incidence of administration-related reactions (ARRs) with subcutaneous Darzalex. Systemic ARRs occurred in 14 patients (7%) in the D-CyBorD group; all were grade 1–2, and the majority occurred during the initial dose administration. A total of 56 deaths occurred in the study (D-CyBorD group, n=27; CyBorD group, n=29).。

Raymond L. Comenzo, Director of the John C. Davis Myeloma and Amyloid Program at Tufts Medical Center and an investigator in the study, stated, “Patients with AL amyloidosis often experience poor outcomes because their symptoms are confused with those of more common conditions, leading to delayed diagnosis. Among patients with AL amyloidosis, treatment of newly diagnosed cases is the most challenging, with many patients not reaching second-line therapy. In the ANDROMEDA study, patients treated with subcutaneous Darzalex demonstrated higher rates of hematologic complete response and significant preservation of major organ function, suggesting that subcutaneous Darzalex may be a treatment for newDiagnosisa promising treatment for patients with AL amyloidosis. These patients are in urgent need of new therapeutic options.”

Janssen Research & Development, Hematology andTumorJessica Vermeulen, M.D., Global Medical Head/Clinical Lead, stated: “There is now an urgent need to provide for those who areDiagnosis"Providing promising therapies for patients with this difficult-to-treat rare disease, as they have no approved treatment options. Our goal is to bring new hope to the treatment journey of patients with AL amyloidosis. We are encouraged by the results generated by Darzalex (an anti-CD38 monoclonal antibody used to treat multiple myeloma), and we look forward to submitting regulatory applications to authorities based on the results of the ANDROMEDA study."

In China, the intravenous (IV) formulation of Darzalex (ZHAOKE®, daratumumab) was approved for marketing in October 2019. This drug is indicated for the monotherapy treatment of adult patients with relapsed and refractory multiple myeloma (MM), specifically those who have received prior therapies including proteasome inhibitors and immunomodulatory agents and experienced disease progression during their last treatment. As the first CD38 monoclonal antibody targeted therapy approved in China, this innovative regimen is poised to redefine the treatment landscape for multiple myeloma domestically.

Darzalex is the first CD38-mediated, cytolytic antibody drug approved globally, with broad-spectrum killing activity. It can target and bind to the CD38 molecule, a transmembrane extracellular enzyme highly expressed on the surface of multiple myeloma cells and various solid tumor cells. By employing multiple immune-mediated mechanisms of action, it induces rapid death of tumor cells, including complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and throughApoptosis(apoptosis). Furthermore, Darzalex has also been demonstrated to targetTumorImmunosuppressive cells in the microenvironment thereby exhibit immunomodulatory activity.

Darzalex was first approved for marketing in November 2015, with sales reaching $2.998 billion in 2019. Currently, the drug has been approved in many countries worldwide for first-line, second-line, and multi-line treatment of multiple myeloma (MM). The specific approved indications vary by country, including: (1) In November 2015, as a monotherapy for adult patients with MM who have previously received at least three prior therapies (including a proteasome inhibitor [PI] and an immunomodulatory agent [IMiD]) or who are double-refractory to PIs and IMiDs; (2) In November 2016, in combination with lenalidomide and dexamethasone, or in combination with bortezomib and dexamethasone, for adult patients with MM who have received at least one prior therapy; (3) In June 2017, in combination with pomalidomide and dexamethasone, for adult patients with MM who have previously received at least two prior therapies (including lenalidomide and a PI); (4) In May 2018, in combination with bortezomib, melphalan, and prednisone, for patients ineligible for autologousStem Cellsadult patients with newly diagnosed multiple myeloma (NDMM) eligible for autologous stem cell transplantation (ASCT); this approval makes Darzalex the first therapy approved for the treatment of NDMMMonoclonal Antibody Drugs(5) In June 2019, in combination with lenalidomide and dexamethasone, for adult patients with newly diagnosed multiple myeloma (MM) who are ineligible for autologous stem cell transplantation (ASCT). (6) In September 2019, in combination with bortezomib, thalidomide, and dexamethasone, for adult patients with newly diagnosed MM who are eligible for ASCT. This approval made Darzalex the first biologic agent approved for use in patients with newly diagnosed MM who are eligible for ASCT.

In February 2019, a split-dosing regimen for Darzalex was also approved in the United StatesFDAApproved. This protocol will allow healthcare professionals to choose, as needed, when treating MM patients, to split the initial intravenous infusion of Darzalex from a single one-time infusion into divided intravenous infusions over two consecutive days.

In May and June of this year, the subcutaneous (SC) formulation of Darzalex (branded as Darzalex Faspro in the United States) received approval in the US and the European Union, becoming the first and only subcutaneous CD38-targeted antibody therapy. Darzalex SC is administered via subcutaneous injection at a fixed dose, with the procedure taking only 3–5 minutes to complete. In contrast, the intravenous (IV) formulation is delivered via infusion, which typically takes several hours. The approval of the SC formulation marks a significant milestone that will help positively transform the lives of patients with multiple myeloma (MM) who rely on Darzalex for treatment. (Bioon.com)

Original Source: Subcutaneous Daratumumab Combination Resulted in Deep and Rapid Hematologic Responses and Improved Clinical Outcomes in the Treatment of Patients with Newly Diagnosed Light Chain (AL) Amyloidosis